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Vertex Submits sNDA for New Kalydeco Indication in Cystic Fibrosis Patients with R117H Mutations

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NEW YORK (GenomeWeb) – Vertex Pharmaceuticals this week said it has submitted a supplemental new drug application with the US Food and Drug Administration for Kalydeco (ivacaftor) as a treatment for cystic fibrosis patients 18 years and older who have the R117H mutation in the CFTR gene.

Vertex estimates there are approximately 300 CF patients who are 18 or older, who have the R117H mutation – the most common residual function mutation.

To support the sNDA, Vertex submitted data from a Phase III trial involving 69 CF patients six and older who had at least one R117H mutation. The study did not meet its primary endpoint of the mean absolute change from baseline in percent predicted forced expiratory volume in one second, or ppFEV1, favoring Kalydeco over placebo across all patients. In a subset of patients, however, those who were 18 years or older, there was a statistically significant improvement in lung function and other secondary endpoints.

Participants in this study could enroll in an open label trial where they received Kalydeco after a washout period of at least three weeks. The mean absolute improvement in lung function for patients 18 years and older after the first dozen weeks was 5.1 percentage points.

In this 24-week rollover study, patients commonly experienced infective pulmonary exacerbations, cough, and headache in similar rates in the Kalyndeco and placebo arms. Around 12 percent of those on Kalydeco experienced serious adverse events, compared to 17 percent in the placebo arm. The most common serious adverse reaction was infective pulmonary exacerbations.

Kalydeco is already approved in the US for CF patients six years and older who have nine CFTR mutations: G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P or G1349D. CF is caused by defects in the CFTR gene, and there are 1,900 known mutations that cause the disease.

CF patients who inherit mutations in the CFTR gene get the life threatening disease. The genetic alteration can lead to faulty CFTR proteins that hinder the ability of patients' cells in organs such as the lungs, to transfer salt and water in and out. This in turn causes sticky mucus to build up in the lungs, leading to infections and damage. Kalydeco is a CFTR "potentiator," that helps keep open CFTR protein channels that so-called "gating" mutations have blocked.

Vertex estimates that 75,000 people in North America, Europe, and Australia have CF. The median age of survival for a CF patient is between 34 and 47 years and the median age of death for those with this condition is mid-20s.

In addition to the submission with the FDA, Vertex said it will submit a marketing authorization application in Europe for Kalydeco in the third quarter of this year for the same indication.

Vertex is also studying Kalydeco in CF patients 12 and older with two copies of the F508del mutation, and recently reported Phase III data in this regard. The company is investigating another agent in the same group called lumacaftor, a CFTR "corrector" that helps CFTR proteins reach the cell surface in patients with mutations that hinder them from doing so.

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